A Closed-Loop Microsystem for Neuromodulation of Reward Circuitry Pedram Mohseni1 and Paul A. Garris2 1 Case Western Reserve University 2 Illinois State University While great strides have been made in our understanding of the basic neurobiology of addiction, many outstanding questions still remain. There is also a grave necessity to develop new treatments, as current options exhibit high recidivism. For good reason, particular attention has focused on the role of dopamine neurons in compulsory drug taking and addictive behavior. One emergent hypothesis is that abused substances usurp reward-processing circuits by hyperactivating phasic dopamine signaling, which leads to altered synaptic plasticity and the overvaluation of cues predicting drug availability. Driving the pursuit of this potentially unifying hypothesis are recent technical advances in microsensors, transgenic animals, and optogenetics. Collectively, these powerful approaches permit high-fidelity dopamine monitoring and ultra-fine molecular control over dopamine neurons and their targets. However, there is a dearth in the current state of technology for dynamic, state-dependent control. Such technology would actively link neuromonitoring and neurostimulation in closed-loop manner to permit extant neural activity and a priori criteria determine the desired outcome. The long-term objective of this research is thus to realize closed-loop devices supporting research in drug abuse and clinical therapies for treating addiction. To this end, an electrical engineer/computer scientist (PI Mohseni) and a neurobiologist/analytical chemist (PI Garris) will collaborate on the present Cutting-Edge Basic Research Awards (CEBRA) proposal to develop a computation and control integrated circuit (IC) for such linking of neuromonitoring and neurostimulation. This IC will incorporate fast- scan cyclic voltammetry (FSCV) at a carbon-fiber microelectrode (CFM), a state-of-the-art neuromonitoring technique with exquisite temporal, spatial, and chemical resolution, and principal component regression (PCR), a chemometrics approach for resolving single analytes from complex neurochemical profiles. The three specific aims are to: (1) develop a sensing, computation, and control IC supporting FSCV at a CFM; (2) test and characterize the IC; (3) pilot dopamine-sensing-based feedback control with the IC for neutralizing activated phasic dopamine signaling. We submit that developing this IC is a transformative step for addiction research, by laying the foundation for novel implantable microsystems supporting applications in biomedical research and ultimately for smart therapeutic neuroprostheses in the clinical realm. Feedback control based on the ability of FSCV and PCR to interrogate the neurochemical activity of a single neuron-type also represents a significant technical advance toward the development of closed-loop devices. This research is additionally innovative, because an IC for neurochemical feedback control has not been realized, and the proposed IC will be capable of modulating both static and dynamic neurochemical activity and accommodating a broad repertoire of analytes important in addiction. This project will also train one doctoral student each in the fields of electrical engineering-computer science and neurobiology-analytical chemistry during its two-year duration.